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Incretin Hormones in Obesity and Related Cardiometabolic Disorders: The Clinical Perspective.

ABSTRACT: The prevalence of obesity continues to grow rapidly worldwide, posing many public health challenges of the 21st century. Obese subjects are at major risk for serious diet-related noncommunicable diseases, including type 2 diabetes mellitus, cardiovascular disease, and non-alcoholic fatty liver disease. Understanding the mechanisms underlying obesity pathogenesis is needed for the development of effective treatment strategies. Dysregulation of incretin secretion and actions has been observed in obesity and related metabolic disorders; therefore, incretin-based therapies have been developed to provide new therapeutic options. Incretin mimetics present glucose-lowering properties, together with a reduction of appetite and food intake, resulting in weight loss. In this review, we describe the physiology of two known incretins-glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and their role in obesity and related cardiometabolic disorders. We also focus on the available and incoming incretin-based medications that can be used in the treatment of the above-mentioned conditions.

SUBMITTER: Michalowska J

PROVIDER: S-EPMC7910956 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Incretin Hormones in Obesity and Related Cardiometabolic Disorders: The Clinical Perspective.

Michałowska Joanna J Miller-Kasprzak Ewa E Bogdański Paweł P

Nutrients 20210125 2

The prevalence of obesity continues to grow rapidly worldwide, posing many public health challenges of the 21st century. Obese subjects are at major risk for serious diet-related noncommunicable diseases, including type 2 diabetes mellitus, cardiovascular disease, and non-alcoholic fatty liver disease. Understanding the mechanisms underlying obesity pathogenesis is needed for the development of effective treatment strategies. Dysregulation of incretin secretion and actions has been observed in o ...[more]

PMID: 33503878

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Project description:BackgroundA complex set of perturbations occur in cytokines and hormones in the etiopathogenesis of obesity and related cardiometabolic conditions such as type 2 diabetes (T2D). Evidence for the genetic regulation of these cytokines and hormones is limited, particularly in African-ancestry populations. In order to improve our understanding of the biology of cardiometabolic traits, we investigated the genetic architecture of a large panel of obesity- related cytokines and hormones among Africans with replication analyses in African Americans.MethodsWe performed genome-wide association studies (GWAS) in 4432 continental Africans, enrolled from Ghana, Kenya, and Nigeria as part of the Africa America Diabetes Mellitus (AADM) study, for 13 obesity-related cytokines and hormones, including adipsin, glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide-1 (GLP-1), interleukin-1 receptor antagonist (IL1-RA), interleukin-6 (IL-6), interleukin-10 (IL-10), leptin, plasminogen activator inhibitor-1 (PAI-1), resistin, visfatin, insulin, glucagon, and ghrelin. Exact and local replication analyses were conducted in African Americans (n = 7990). The effects of sex, body mass index (BMI), and T2D on results were investigated through stratified analyses.ResultsGWAS identified 39 significant (P value < 5 × 10-8) loci across all 13 traits. Notably, 14 loci were African-ancestry specific. In this first GWAS for adipsin and ghrelin, we detected 13 and 4 genome-wide significant loci respectively. Stratified analyses by sex, BMI, and T2D showed a strong effect of these variables on detected loci. Eight novel loci were successfully replicated: adipsin (3), GIP (1), GLP-1 (1), and insulin (3). Annotation of these loci revealed promising links between these adipocytokines and cardiometabolic outcomes as illustrated by rs201751833 for adipsin and blood pressure and locus rs759790 for insulin level and T2D in lean individuals.ConclusionsOur study identified genetic variants underlying variation in multiple adipocytokines, including the first loci for adipsin and ghrelin. We identified population differences in variants associated with adipocytokines and highlight the importance of stratification for discovery of loci. The high number of African-specific loci detected emphasizes the need for GWAS in African-ancestry populations, as these loci could not have been detected in other populations. Overall, our work contributes to the understanding of the biology linking adipocytokines to cardiometabolic traits.

Project description:Incretin hormones (glucose-dependent insulinotropic polypeptide [GIP] and glucagon-like peptide-1 [GLP-1]) play a role in the pathophysiology of type 2 diabetes. Along with their derivatives they have shown therapeutic success in type 2 diabetes, with the potential for further improvements in glycaemic, cardiorenal and body weight-related outcomes. In type 2 diabetes, the incretin effect (greater insulin secretory response after oral glucose than with 'isoglycaemic' i.v. glucose, i.e. with an identical glycaemic stimulus) is markedly reduced or absent. This appears to be because of a reduced ability of GIP to stimulate insulin secretion, related either to an overall impairment of beta cell function or to specific defects in the GIP signalling pathway. It is likely that a reduced incretin effect impacts on postprandial glycaemic excursions and, thus, may play a role in the deterioration of glycaemic control. In contrast, the insulinotropic potency of GLP-1 appears to be much less impaired, such that exogenous GLP-1 can stimulate insulin secretion, suppress glucagon secretion and reduce plasma glucose concentrations in the fasting and postprandial states. This has led to the development of incretin-based glucose-lowering medications (selective GLP-1 receptor agonists or, more recently, co-agonists, e.g. that stimulate GIP and GLP-1 receptors). Tirzepatide (a GIP/GLP-1 receptor co-agonist), for example, reduces HbA1c and body weight in individuals with type 2 diabetes more effectively than selective GLP-1 receptor agonists (e.g. semaglutide). The mechanisms by which GIP receptor agonism may contribute to better glycaemic control and weight loss after long-term exposure to tirzepatide are a matter of active research and may change the pessimistic view that developed after the disappointing lack of insulinotropic activity in people with type 2 diabetes when exposed to GIP in short-term experiments. Future medications that stimulate incretin hormone and other receptors simultaneously may have the potential to further increase the ability to control plasma glucose concentrations and induce weight loss.

Project description:BackgroundOverweight and obesity are global health issues, impacting a significant portion of young adults. Obesity is a complex condition influenced by genetics and environmental factors, leading to increased susceptibility to cardiovascular diseases (CVDs), hypertension, dyslipidemia, and insulin resistance. Irisin, a protein derived from the cleavage of fibronectin type III domain-containing protein 5, may have relationship with these cardiometabolic diseases.ObjectiveThis systematic review aims to examine the relationship between serum irisin levels and obesity, particularly in individuals predisposed to cardiovascular risk factors.MethodsA thorough literature search was conducted in multiple databases, including "Science Direct," "Scopus," "PubMed," and "Lilacs," from July 2020. Inclusion criteria encompassed subjects with metabolic disorders (with or without obesity, BMI ≥30 kg/m2), clinical trials, and observational studies published between 2010 and June 2020. Exclusion criteria were animal studies, meta-analyses, systematic reviews, studies evaluating only healthy subjects, and those investigating disorders beyond cardiometabolic diseases.ResultsOut of 151 identified articles, 30 met the inclusion criteria. These studies, published between 2013 and 2020, assessed adults (≥21 years) and included 26 observational studies and 4 clinical trials (n = 7585 subjects). All studies examined irisin's role in obesity and CVDs, often including associated diseases such as type 2 diabetes and hypertension. Despite varying sample sizes, the samples within the articles were homogeneous. Observational studies exhibited a low risk of bias in at least 60% of the evaluated domains. Clinical trials demonstrated a low risk of bias in at least 50% of the domains. Limitations. Although the systematic review provides valuable insights, it is limited by the available literature and the varying methodologies used across studies.ConclusionThe review suggests that irisin plays a significant role as both a preventive measure and a biomarker for comorbidities linked to obesity and cardiometabolic disorders. Future research should focus on standardized irisin measurement methods and diverse populations to further elucidate its mechanisms of action.

Project description:BackgroundStudies in adults indicate that macronutrient ingestion yields an acute anti-resorptive effect on bone, reflected by decreases in C-terminal telopeptide (CTX), a biomarker of bone resorption, and that gut-derived incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), facilitate this response. There remain knowledge gaps relating to other biomarkers of bone turnover, and whether gut-bone cross-talk is operative during the years surrounding peak bone strength attainment. This study first, describes changes in bone resorption during oral glucose tolerance testing (OGTT), and second, tests relationships between changes in incretins and bone biomarkers during OGTT and bone micro-structure.MethodsWe conducted a cross-sectional study in 10 healthy emerging adults ages 18-25 years. During a multi-sample 2-hour 75 g OGTT, glucose, insulin, GIP, GLP-1, CTX, bone-specific alkaline phosphatase (BSAP), osteocalcin, osteoprotegerin (OPG), receptor activator of nuclear factor kappa-β ligand (RANKL), sclerostin, and parathyroid hormone (PTH) were assayed at mins 0, 30, 60, and 120. Incremental areas under the curve (iAUC) were computed from mins 0-30 and mins 0-120. Tibia bone micro-structure was assessed using second generation high resolution peripheral quantitative computed tomography.ResultsDuring OGTT, glucose, insulin, GIP, and GLP-1 increased significantly. CTX at min 30, 60, and 120 was significantly lower than min 0, with a maximum decrease of about 53 % by min 120. Glucose-iAUC0-30 inversely correlated with CTX-iAUC0-120 (rho = -0.91, P < 0.001), and GLP-1-iAUC0-30 positively correlated with BSAP-iAUC0-120 (rho = 0.83, P = 0.005), RANKL-iAUC0-120 (rho = 0.86, P = 0.007), and cortical volumetric bone mineral density (rho = 0.93, P < 0.001).ConclusionsGlucose ingestion yields an anti-resorptive effect on bone metabolism during the years surrounding peak bone strength. Cross-talk between the gut and bone during this pivotal life stage requires further attention.

Dataset Information

Incretin Hormones in Obesity and Related Cardiometabolic Disorders: The Clinical Perspective.

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Incretin Hormones in Obesity and Related Cardiometabolic Disorders: The Clinical Perspective.

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